REVIEW

Defining the phenotype, pathogenesis and treatment of Crohn’sdisease associated spondyloarthritis

Anand Kumar1 • Dana Lukin1 • Robert Battat1 • Monica Schwartzman2 •

Lisa A. Mandl2 • Ellen Scherl1 • Randy S. Longman1

Received: 3 April 2020 / Accepted: 14 April 2020 / Published online: 4 May 2020

� The Author(s) 2020

Abstract Peripheral and axial spondyloarthritis are the most

common extra-intestinal manifestations reported in patients

with Crohn’s disease. Despite the frequency of Crohn’s dis-

ease associated spondyloarthritis, clinical diagnostic tools are

variably applied in these cohorts and further characterization

with validated spondyloarthritis disease activity indexes are

needed. In addition, the pathogenesis of Crohn’s disease as-

sociated spondyloarthritis is not well understood. Evidence of

shared genetic, cellular, and microbial mechanisms underly-

ing both Crohn’s disease and spondyloarthritis highlight the

potential for a distinct clinicopathologic entity. Existing

treatment paradigms for Crohn’s disease associated spondy-

loarthritis focus on symptom control and management of

luminal inflammation. A better understanding of the under-

lying pathogenic mechanisms in Crohn’s disease associated

spondyloarthritis and the link between the gut microbiome

and systemic immunity will help pave the way for more tar-

geted and effective therapies. This review highlights recent

work that has provided a framework for clinical characteri-

zation and pathogenesis of Crohn’s disease associated

spondyloarthritis and helps identify critical gaps that will help

shape treatment paradigms.

Keywords Crohn’s disease � Spondyloarthritis �Microbiome

Abbreviations

5ASA 5-Aminosalicylate

anti-

TL1A

Anti-tumor necrosis factor-like cytokine 1A

AS Ankylosing spondylitis

ASAS Assessment of SpondyloArthritis international

Society

ASDAS Ankylosing Spondylitis Disease Activity

BASDAI Bath Ankylosing Spondylitis Disease Activity

Index

CD Crohn’s disease

CD-SpA CD-associated spondyloarthritis

CD4 Cluster of differentiation-4

COX Cyclo-oxygenase

CRP C-reactive protein

CX3CR1 C-X3-C motif chemokine receptor

EIM Extra-intestinal manifestation

GM-CSF Granulocyte monocyte-colony stimulating

factor

HLA Human leucocyte antigen

IBD Inflammatory bowel disease

Ig Immunoglobulin

IL Interleukin

ILC Innate lymphoid cells

JAK Janus Kinase

KIR3DL2 Killer cell immunoglobulin-like receptor

3DL2

MHC Major histocompatibility complex

MNP Mononuclear phagocytes

MRI Magnetic resonance imaging

NSAID Non-selective anti-inflammatory drugs

PsA Psoriatic arthritis

PPARg Peroxisome proliferator activated receptor

gamma

PSpARC Peripheral SpA response criteria

& Randy S. Longman

ral2006@med.cornell.edu

1 Jill Roberts Center for Inflammatory Bowel Disease, Weill

Cornell Medicine, 413 E 69th Street, 7th Floor, New York,

NY 10021, USA

2 Hospital for Special Surgery, Weill Cornell Medicine,

New York, NY, USA

123

J Gastroenterol (2020) 55:667–678

https://doi.org/10.1007/s00535-020-01692-w

SAS Sulfasalazine

SpA Spondyloarthritis

RA Rheumatoid arthritis

Th T helper cells

TNF Tumor necrosis factor

Treg Regulatory T cells

TYK2 Tyrosine kinase 2

UC Ulcerative colitis

VLP Viral like particles

Introduction

Crohn’s disease (CD) has long been recognized to co-exist

with systemic inflammation resulting in extra-intestinal

manifestations (EIMs). Population studies have suggested

that up to 30–40% of patients with active inflammatory

bowel disease (IBD) experience EIMs [1, 2]. Arthritis is

the most common EIM reported in IBD, which is more

prevalent in CD than in ulcerative colitis (UC) [3-5]. In

most cases, symptoms of spondyloarthritis (SpA) follow

the diagnosis of IBD; however, in nearly 20% cases, joint

inflammation precedes initial diagnosis of intestinal disease

[6, 7]. Although both peripheral and axial joints can be

involved, inflammation of the sacroiliac joints is classically

associated with IBD. Despite the frequency of inflamma-

tory joint symptoms, CD-associated seronegative spondy-

loarthritis (CD-SpA) is often under-diagnosed and

inadequately assessed by gastroenterologists [3, 8]. This

under-diagnosis of CD-SpA limits the ability to track

symptom response and ultimately impedes delivery and

optimization of therapy. Refined clinical diagnostic criteria

and disease activity indices have helped guide recent

studies in elucidating the pathogenesis of CD-SpA, offer-

ing critical insight into treatment selection for this distinct

clinicopathologic entity. This review will highlight recent

progress in clinical characterization and pathogenesis of

CD-SpA, the impact this has on treatment paradigms, and

critical gaps that need to be addressed.

Classifying and characterizing spondyloarthritisin Crohn’s disease

Even early descriptions of CD recognized the co-occur-

rence of intestinal inflammation with arthritis. These clin-

ical findings of joint inflammation reflect a spectrum of

SpA characterized based on the involvement of peripheral

or axial joints. Peripheral spondyloarthritis can be paucia-

rticular (previously called Type I) or polyarticular (previ-

ously called Type II) joint inflammation [4, 9, 10]. Axial

spondyloarthritis, traditionally referred to as ankylosing

spondylitis (AS), includes inflammation of the spine and/or

sacroiliac joint. Although earlier literature distinguished

clinical SpA based on concordance or discordance with

intestinal disease activity, histologic and molecular evi-

dence of subclinical intestinal inflammation support a more

inclusive spectrum of disease linking gut and systemic

immunity [11, 12]. Reflecting this underlying state of

systemic inflammation, spondyloarthritis frequently co-

occur with other EIMs including erythema nodosum and

uveitis. While this overall description serves as a frame-

work for a spectrum of musculoskeletal symptoms asso-

ciated with CD, challenges exist in defining both clinical

disease burden and underlying pathogenic mechanisms that

are needed to guide treatment strategies for CD-SpA.

One challenge in assessing the overall burden of CD-

SpA is the lack of uniformity in applying conventional

clinical definitions of SpA. Strict characterization of point

prevalence of peripheral arthritis in an IBD cohort on

physical exam can be very low (\ 1%), however inclusion

of patient reported self-limited episodes increases the

prevalence considerably (up to 12%) [13]. Including

patient reported episodes introduces the risk of reporting

non-inflammatory arthropathies in these prevalence esti-

mates. As such, the wide variability in prevalence of IBD

associated peripheral arthritis (5–44%) and axial inflam-

mation (1–25%) reflect this lack of uniformity in clinical

disease characterization [3-5, 13], likely arising from the

use of non-standardized disease definitions, not distin-

guishing non-inflammatory arthralgia from arthritis, and

the lack of rheumatologic evaluation. The recent European

Crohn’s and Colitis Organization (ECCO) guidelines have

also addressed this issue, highlighting a need to ensure

accurate identification of true inflammatory arthritis [10].

Criteria established by the Assessment of Spondy-

loArthritis international Society (ASAS) defines both axial

and peripheral SpA. In the context of CD, ASAS criteria

define axial SpA as sacroiliitis on magnetic resonance

imaging (MRI) or HLA-B27 positivity with one other SpA

feature such as inflammatory back pain [14]. Similarly in

the context of CD, ASAS criteria define peripheral SpA as

the presence of peripheral arthritis, or enthesitis or

dactylitis [15] (Table 1). These clinical criteria demonstrate

strong sensitivity and specificity for correlation with clin-

ical assessment by rheumatologists [16], but have been

applied variably in IBD cohorts.

Retrospective analysis of longitudinal follow up studies

using ASAS criteria to characterize SpA in IBD cohorts

provided estimates of axial SpA (7.7–12.3%) and periph-

eral SpA (9.7–27.9%) [17, 18]. These studies serve as a

strong basis for validating the use of modified ASAS

guidelines in defining CD-SpA in future research.

In addition, there is a significant unmet need for the

uniform application of joint disease activity indices in CD-

668 J Gastroenterol (2020) 55:667–678

123

SpA to establish validity, reliability, and responsiveness for

clinical evaluation as well as endpoint assessment in

research studies. The Bath Ankylosing Spondylitis Disease

Activity Index (BASDAI) is a patient-reported tool that has

been clinically validated for assessment of inflammatory

activity and response to therapy in both axial and periph-

eral SpA [19-21]. Ankylosing Spondylitis Disease Activity

(ASDAS) includes patient-reported individual and a global

activity score and either c-reactive protein (CRP) or ery-

throcyte sedimentations rate (ESR) [22]. While the inclu-

sion of CRP or ESR provides an objective measurement of

inflammatory burden, there are limitations to assessments

based on the subjective patient-reported symptom scores.

Although BASDAI and ASDAS have also been used to

assess arthritis activity and response to treatment in IBD-

related SpA [23, 24], these scores do not always correlate

with joint inflammatory activity in IBD [25, 26]. Addi-

tionally, these scores are validated mostly in axial disease

and while they may similarly provide an accurate measure

of peripheral disease, patients with predominantly periph-

eral SpA may benefit from a more focused evaluation [27].

Peripheral joint characterization included in more exten-

sive exams including Peripheral SpA Response Criteria

(PSpARC40) may more accurately assess response, but the

required joint examinations by an expert rheumatologist

make the broader use of these instruments in gastroen-

terology practices less practical [28]. Finally, MRI has

revolutionized assessment of SpA over the last two dec-

ades, but no validated criteria have yet been developed to

assess disease severity or response to therapy in IBD. Thus,

there remains a need for studies to validate these indices in

CD-SpA and to correlate with pathogenic biomarkers to

help guide therapy.

Elucidating the pathogenesis of spondyloarthritisin Crohn’s disease

The pathogenesis of CD-SpA remains poorly understood.

A variety of pathogenic mechanisms have been proposed

including those which result from an extension of gut-

specific inflammatory processes as well as non-specific

alterations in the systemic inflammatory milieu [10]

(Fig. 1). The strongest genetic susceptibility to SpA lies

within the major histocompatibility complex (MHC) class I

locus with human leucocyte antigen gene (HLA)-B27

conferring the highest genetic risk association to date [29].

Genetic risk variants individually associated with either

SpA or IBD overlap significantly in the interleukin (IL)

23-IL17 pathway, although no specific genetic markers of

IBD-associated SpA have been defined [30]. These findings

highlight the likely interaction of multiple genetic path-

ways as well as the potential role for environmental and/or

microbial factors, which synergistically or independently

act to modulate inflammation in a genetically susceptible

host. Here, we will focus on the IL23-IL17 pathway and its

potential intersection with the gut microbiome.

Elucidating the cellular mechanism for IL-23

dependent inflammation in CD-SpA

Early studies demonstrated that susceptibility variants in

the IL23R locus were associated with IBD and SpA inde-

pendently [31]. These studies initially postulated a role of

IL-23 in supporting IL-17 producing Th17 CD4? T cells

[32]. IL-17 as an effector molecule can play a key role in

neutrophil recruitment and sustaining the inflammatory

environment. Supporting the importance of IL-17, analysis

of both synovial tissue and circulating blood in patients

with inflammatory arthritis or AS showed an upregulation

of Th17 cells which positively correlated with joint disease

activity scores [33-36]. Linkage of susceptibility variants in

the IL17 pathway (RUNX3, IL23R, IL6R, IL1R2, IL12B,

TYK2) [37] further support the potential pathogenic role

Table 1 Classification criteria for CD-SpA adapted from the Assessment of SpondyloArthritis international Society (ASAS) criteria [14, 15]

Axial CD-SpA Peripheral CD-SpA

Inflammatory back paina in a patient with CD

AND

Sacroiliitis on imagingb

OR

HLA B-27 antigen positivity

Arthritis and/or dactylitis and/or enthesitis in a patient with CD

AND

Exclusion of other specific forms of inflammatory joint disease

CD Crohn’s disease, CD-SpA Crohn’s disease associated spondyloarthritis, SpA spondyloarthritisaInsidious onset, chronic back/buttock pain with morning stiffness lasting C 30 min, improvement with activity and nocturnal exacerbationbActive inflammation on MRI highly suggestive of sacroiliitis OR definite radiographic sacroiliitis according to modified New York criteria

J Gastroenterol (2020) 55:667–678 669

123

for this subset. Despite initial reports of molecular mimicry

as the mechanism underlying HLA-B27 dependent disease

[38], more recent work showed that misfolding of HLA-

B27 can lead to increased IL-23 and enable HLA-

B27 homodimers to bind KIR3DL2 on IL-17? CD4? cells

in blood and synovium [39-41]. These findings link the

strong HLA-B27 association seen in AS with the IL-23-

Th17 pathway [42].

Despite the initial focus on Th17 immunity, other cells

in addition to CD4? T cells were found to be predominant

producers of IL-17. CD8? T cells in particular were shown

to have higher IL-17 production in the peripheral blood and

synovial joint in psoriatic arthritis (PsA), which is a type of

SpA affecting primarily the peripheral joints [43]. Of note,

this finding was seen in SpA, but not in rheumatoid arthritis

(RA), reflecting the specific association of SpA with MHC

class I alleles. Experimental models of enthesitis further

highlighted the role of non-conventional IL-23R responsive

T cells [44], but their potential role in human disease is still

not clear.

Although IL-17 is a main effector cytokine downstream

of IL-23, other cell types as well as effector molecules exist

in this pathway, demonstrating the complexity of their

potential contribution to SpA. In particular, the discovery

of group 3 innate lymphoid cells (ILCs) defined a unique

innate cell type capable of producing IL-22 and GM-CSF

Fig. 1 Pathogenic mechanisms of Crohn’s-associated spondyloarthri-

tis. Ag-Ab antigen–antibody complex, CARD15 Caspase recruitment

domain-containing protein 15, CD Crohn’s disease, CD-SpA Crohn’s

disease associated spondyloarthritis, GM-CSF granulocyte monocyte

colony stimulating factor, HLA human leukocyte antigen, IBD

inflammatory bowel disease, IL Interleukin, ILC innate lymphoid

cell, IFN interferon, LPS lipopolysaccharide, MNP mono-nuclear

phagocytes, SpA spondyloarthritis, TNF tumor necrosis factor, Th

helper T cells. Genetic susceptibility: presence of HLA genes (B27,

B35, B44) and polymorphisms in IL-23R, IL-12B, STAT3, and

CARD9, CARD15 genes increase the susceptibility of host to both

IBD and SpA. Intestinal dysbiosis: abundance of Proteobacteria,

Enterobacteriaceae, Ruminococcus gnavus and a reduction in Bac-

teroidetes in patients with CD-SpA. Additionally, abundance of

Dialister, R. gnavus, Prevotella (axial SpA) seen in SpA. Molecular

mimicry: cross reactivity between peptide sequences common

between enteric bacteria and host HLA. Autoimmune gut inflamma-

tion in CD triggered by genetic and environmental factors leading to

activation of IL23-IL17 axis and intestinal phagocytic cells. Exten-

sion of immune response from gut to joint could occur through:

Molecular mimicry; Trafficking of activated immune cells (T cells,

macrophages, innate lymphoid cells) facilitated by: ectopic expres-

sion of gut-specific chemokines (CCL25), adhesion molecules

(MAdCAM, ICAM, E-cadherin) and integrins (a4b7, aEb7) in the

joint; binding to non-gut-specific adhesion molecules (VAP-1) and

chemokine receptors (CXCR3, CCR5); Intestinal mucosal barrier

dysfunction and translocation of microbial antigens/products (LPS);

Increased inflammatory mediators and proinflammatory cytokines

(IL-6, TNFa, IFNc,) in serum; Circulating autoantibodies with

epitopes shared between the gut and joint

670 J Gastroenterol (2020) 55:667–678

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in response to IL-23 [45]. The discovery of ILCs coupled

with reports of discordance between IL23A and IL17 in the

ileal tissue, raised this possibility that IL-23 responsive

ILCs may play a critical role in SpA independent of IL17

[46]. Intestinal CX3CR1? mononuclear phagocytes

(MNPs) are a main source of IL-23 that activate ILCs, and

these MNPs are increased in patients with AS [47]. In

addition, MNP production of tumor necrosis factor (TNF)-

like cytokine 1A (TL1A), which is increased in the syn-

ovium of patients with AS, synergizes with IL-23 to reg-

ulate the production of IL-22 [48]. These finding highlight

an array of innate effectors linking IL-23 with gut-joint

inflammation.

Thus, although these findings highlight a strong genetic

basis for the IL-23 pathway in CD-SpA, the cellular

mechanism and key effectors molecules still need to be

clarified. With the development of biologic therapies tar-

geting specific aspects of these pathways, a mechanistic

understanding will be essential to developing strategic

treatment paradigms in CD-SpA. Furthermore, given the

overlap of genetic risk in CD and SpA, it will be important

to understand the underlying intestinal triggers of SpA.

Understanding the potential role for the microbiome

in CD-SpA

Even before the discovery of the IL-23 dependence of

disease pathogenesis, the gut was recognized as a potential

portal for SpA initiation. Subclinical luminal inflammation

is seen in 60% of patients with SpA and defined by key

histologic features in SpA [46, 49]. Fecal calprotectin is a

promising strategy to identify these patients [50]. This led

to the hypothesis that opportunistic pathobionts in the gut

could potentially trigger an immune response at a distant

extra-intestinal site in a genetically predisposed host. Since

then, several studies have been conducted to explain the

mechanisms that could help explain this phenomenon.

The microbiome was viewed as an early potential trigger

for seronegative SpA, partly due to the association of

enteric pathogens such as Salmonella, Campylobacter,

Yersinia and Shigella in reactive arthritis. Early clinical

data revealed a potential association between fecal Kleb-

siella and AS [51]. Cross-reactivity of HLA-B27 with

Klebsiella supported a model of molecular mimicry in

which the amino acid sequence, QTDRED, present in

HLA-B27 was found to have similarity with nitrogenase

reductase enzyme in Klebsiella [38]. This link was further

supported by studies of HLA-B27 transgenic rats which

when re-derived under germ-free conditions showed

attenuation in AS [52, 53]. Although subsequent clinical

studies did not uniformly support this association of SpA

with Klebsiella, more recent studies using high throughput

sequencing technology have allowed for more complete

microbiome analysis. In particular, the mucosal-associated

microbiome from ileal biopsy of patients with new onset

treatment- naı̈ve SpA (without IBD) showed a linear cor-

relation between the abundance of the genus Dialister with

both clinical disease activity (measured by ASDAS) and

joint tissue inflammation [54]. Additional alterations have

been noted in the fecal microbiota of patients with SpA,

most notably the increase in Ruminococcus gnavus [55].

These changes also correlate with clinical disease activity

(measured by BASDAI). Although intestinal inflammation

was not assessed, the abundance of R. gnavus was also

higher in the subset of patients with IBD-associated SpA.

The expansion of Ruminococcus may be unique to axial

SpA as cohort analysis of psoriatic arthritis, in contrast,

showed a reduction in Ruminococcus and Akkermansia

[56]; however, medication treatment of psoriatic arthritis

with non-selective anti-inflammatory drugs (NSAIDs) or

methotrexate could have impacted these findings. Large

metagenomic analysis of 211 participants from China

demonstrated significant alterations in the microbiome in

patients with AS characterized by an increase in Prevotella

species [57]. The increase in Prevotella copri also seen in

RA may reflect a shared mechanism underlying joint

inflammation [58]. Similarly, an increased abundance of

Clostridiaceae was shared by both IBD-associated

arthropathy and RA patients and suggests a potentially

common microbial link for inflammatory arthritis [59].

Collectively, these studies support a correlation between

the gut microbiome and axial SpA, but further studies are

needed to assess the impact of geography, diet, and med-

ication in the diagnostic and therapeutic potential of these

biomarkers.

Several recent studies have revealed potential mecha-

nisms of microbial impact on systemic inflammation. For

example, strain specific lipoglycans from R. gnavus have

been shown to act as potent antigens with both diagnostic

and pathogenic implications for systemic inflammatory

disease [60], highlighting the need for strain level charac-

terization in further defining this clinical association. In

addition, the functional characteristics of the microbial taxa

in the intestinal environment may dictate immune out-

comes. Rat models of HLA-B27 disease show a signifi-

cantly higher level of Akkermansia colonization and

increased frequency of IgA coating of fecal bacteria with

disease activity [61]. These findings illustrate a non-

specific contribution of a mucinophilic pathobiont which

may correlate HLA type with increased inflammatory tone

of Th17 signatures in shared genetic risk pathways [62].

Moreover, the increased abundance of both E. coli and

Prevotella in ileal samples from AS mechanistically reg-

ulated zonulin and epithelial permeability [63]. The com-

munity effect of this dysbiosis, therefore, potentiates the

impact of opportunistic pathobionts.

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123

We have recently evaluated the contribution of the

microbiome in IBD-associated peripheral SpA [20]. Using

fecal samples from 59 IBD patients with or without SpA

defined by ASAS criteria, our results revealed an increased

abundance of Proteobacteria, specifically Enterobacteri-

aceae, and a reduction in Bacteroidetes in patients with

CD-SpA compared to active CD alone. Moreover, the

abundance of Enterobacteriaceae linearly correlated with

SpA activity measured using BASDAI. No differences

were observed between UC-associated SpA and UC alone

suggesting differential contribution of either genetic or

microbial pathways specific to CD. To further define

immunologically relevant strains, we performed IgA-Seq

(or Bug-FACS) in which IgA coated microbes were sorted

and sequenced. Analysis of clonal isolates revealed the

expansion of adherent-invasive E. coli (AIEC) in the IgA-

coated fraction of patients with CD-SpA compared to CD

alone. These isolates are characterized by their ability to

attach to mucosal surfaces and stimulate immune respon-

ses. AIEC-specific IgG in the serum was higher in patients

with CD-SpA compared to CD supporting systemic impact

of particular pathobionts [20]. However, further charac-

terization is needed to understand the role for direct

microbial translocation or local immune cell activation that

triggers systemic joint inflammation.

An important issue arising from the potential contribu-

tion of the microbiome in immune regulation is the role for

strain level differences. For R. gnavus, overall abundance

in the intestine correlated with serum antibodies to only 1/8

R. gnavus strains tested [60]. Akkermansia muciniphila is a

robust inducer of T follicular helper cells and systemic IgG

in mouse models, but the potential contribution of strain

variability is not known [64]. AIEC contains multiple

virulence associated factors which may contribute,

including the long polar fimbriae that is associated with

mucosal attachment and may regulate induction of

cytokines by macrophages [65]. In addition, utilization of

propanediol as a carbon source by AIEC impacts mucosal

attachment and macrophage survival [66] and isolates

capable of this are expanded in CD-SpA, but the contri-

bution of this metabolic function to local and systemic

immunity is not well known. These and other strain specific

factors may help reveal diagnostic and therapeutic micro-

bial targets of systemic immunity in CD-SpA.

Finally, the impact of non-bacterial constituents of the

microbiome including the mycobiome and virome in IBD-

associated SpA is not well studied. Fungal dysbiosis in CD

is characterized by restricted overall diversity and an

expansion in Candida spp. [67]. Circulating anti-S. cere-

visiae antibody levels are elevated in patients with CD, but

the pathogenic contribution to either intestinal or systemic

inflammation is not clear. Fungal elements such as curdlan

are critical in regulating systemic inflammation in animal

models of arthritis [68]. A recent study in patients with AS

suggest higher levels of Ascomycota and decreased abun-

dance of Basidiomycota, but the sample size was limited

[69] and more studies are needed to assess a functional

contribution. Similarly, our understanding of the viral

contribution is limited. An expansion of viral like particles

(VLP) or bacteriophage occurs during active IBD [70]. In

pre-clinical models, these VLPs may directly activate the

immune response and lower VLP levels correlate with

clinical response to fecal transplant in ulcerative colitis

[71], but the impact of the intestinal virome in IBD-asso-

ciated SpA needs to be investigated in clinically pheno-

typed cohorts. Further studies elucidating the potential

contribution of various microbiome-associated pathways in

IBD-associated SpA will help to guide development of

diagnostic and therapeutic targets.

Treatment paradigms for CD-SpA

The progress reviewed above in establishing clinical cri-

teria and elucidating a mechanistic understanding of the

pathogenesis of CD-SpA may allow for rational selection

of treatment. Besides the gold standard tumor necrosis

factor a (TNF) antagonist therapy for SpA, recent com-

mercialization of other biologic therapies targeting a4b7-

mediated trafficking of lymphocytes (vedolizumab) and the

p40 subunit of IL12/23 (ustekinumab) may help personal-

ize treatment of CD-SpA. However, since there is little

direct evidence to support the efficacy of these agents in

co-existing IBD and SpA, current treatment strategies are

extrapolated from independent studies in SpA [such as AS

(axial) and PsA (primarily peripheral SpA)] and IBD or

from limited data from post hoc analysis of therapeutic

drug trials in IBD (Table 2).

Non-selective anti-inflammatory drugs (NSAIDs) are

the first line of therapy in patients with SpA. While non-

selective cyclo-oxygenase (COX) inhibitors are generally

contraindicated in patients with IBD due the risk of disease

exacerbation [72], two clinical trials found selective COX-

2 inhibitors to be safe and effective in the short-term

treatment of inactive IBD [73, 74]. While routine NSAID

therapy is generally avoided in IBD patients due to concern

for potential deleterious effects on the gut mucosa [75],

there is growing evidence that COX-2 inhibitors, and

specifically celecoxib, are safe and effective.

Sulfasalazine (SAS) is one of the disease modifying

drugs effective in treating peripheral arthritis symptoms of

IBD, however is not effective in axial-SpA [76]. Although

one of the oldest medicines used for the treatment of CD,

the mechanism of SAS’s effect is not clear. SAS is a pro-

drug that is cleaved by azo-reductase produced by the

colonic microbiota into sulfapyridine and

672 J Gastroenterol (2020) 55:667–678

123

5-aminosalicylate (5-ASA) released into the distal intes-

tine. It remains unclear if there is a role of one or more gut

microbe in this activation process of SAS. While 5-ASA

may offer the mechanistic benefit to mucosal healing acting

through PPARc (peroxisome proliferator activated receptor

gamma) [77, 78], sulfapyridine inhibits bacterial folic acid

synthesis. The specific target of sulfapyridine’s anti-bac-

terial effect in the microbiome is not known. In addition to

understanding the therapeutic mechanism of its impact,

another consideration is variability in dosing. While

rheumatologists frequently treat with 2 g daily, the gas-

troenterology literature supports the use of 4–6 g daily for

active symptoms [79].

TNF antagonist therapy has been a mainstay of therapy

both for SpA and CD. The efficacy of TNFa blockade

underlies the likely pleiotropic effect of TNFa on many

shared pathways. Indeed, the efficacy of anti-TNFa therapy

in AS correlates with the reduction of Th17 cells in the

peripheral blood following treatment [34]. Despite this

response in the peripheral blood, it is not clear that this

reflects tissue activity of TNF antagonists in IBD-associ-

ated SpA. Systematic reviews of TNF antagonist therapy

support the general efficacy of TNFa blockade in IBD-

associated EIMs [80, 81], including axial and peripheral

SpA. However, the interventional studies that reported

efficacy of infliximab, adalimumab and certolizumab pegol

in the treatment of CD-associated arthritis did not utilize

objective criteria for diagnosis (e.g. ASAS) or to define

response/ remission of joint disease (e.g. ASDAS) [80, 82].

While limited study data are available to characterize the

impact of joint disease activity [23, 83], these biologics are

considered first line therapy for IBD-associated SpA.

Vedolizumab is approved for the induction and main-

tenance of remission in UC and CD. Although initially

discovered and marketed for gut selectivity, vedolizumab

(anti-a4b7) may also impact systemic immunity. One

theory is that blocking the homing of a4b7 into the tissue

increases the abundance of these effectors in the peripheral

blood, thereby enhancing systemic immune activation. In

one study, HLA-B27 negative de novo or flare of inactive

SpA occurred in 11 patients achieving remission of luminal

symptoms with vedolizumab [84]. Moreover, compared to

patients receiving anti-TNF therapies, IBD patients

receiving vedolizumab were more likely to develop EIMs

including arthropathy [85]. Despite these findings, post-hoc

analysis of the GEMINI trials revealed reduced incidence

of arthritis in CD (HR 0.14, 95% CI 0.05–0.35) and no

increase in the incidence of arthritis in UC patients treated

with vedolizumab versus placebo [86]. Similarly, in the

OBSERV-IBD cohort, extra-intestinal inflammation

Table 2 Pharmacologic treatments for CD-SpA

Axial CD-SpA Peripheral CD-SpA

Currently approved therapies

Short term NSAIDs if CD is in remissiona Short term NSAIDs if CD is in remissiona

Anti-TNFa therapy:

Infliximab

Adalimumab

Certolizumab pegol

Local steroid injection for pauciarticular or short-term oral steroid for polyarticular

peripheral SpA

Sulfasalazine

Methotrexate

Anti-TNFa therapy: Infliximab, adalimumab, certolizumab pegol

No IL12/23 inhibitor therapy is proven beneficial in

axial SpA

Anti IL12/23: Ustekinumab

Other therapies under investigation/development

Selective JAK-1 inhibitor: Upadacitinib and filgotinib (successful phase 2 trials in AS, PsA and CD; positive results in phase 3 trial of

upadacitinib in PsA. Ongoing phase 3 trial in CD)

a4b7 anti-integrin: vedolizumab

Approved for treatment of moderate-to-severe CD. Based on recent a systematic review, may be effective in preventing onset of arthritis in CD,

however, may not be effective in improving co-existing arthritis

Therapies under investigation:

S1P1 receptor modulator—ozanimod, etrasimod

Anti-TNF like cytokine 1A (anti-TL1A) therapy

Fecal microbiota transplant

Combination biologic therapy (combining two or more biologics with different mechanism of action)

CD Crohn’s disease, CD-SpA Crohn’s disease associated spondyloarthritis, IL interleukin, JAK Janus kinase, PsA psoriatic arthritis, S1P1

Sphingosine 1-phosphate-1, SpA spondyloarthritis, TNFa tumor necrosis factor-alphaaTypically\ 15 days and should be avoided in active IBD

J Gastroenterol (2020) 55:667–678 673

123

including joint inflammation improved in parallel with

bowel disease, however 13% of patients without EIMs at

baseline developed non-inflammatory arthralgia [87]. More

recently, a systematic review of 11 studies where vedoli-

zumab was used for EIMs in IBD, demonstrated no effect

on pre-existing arthralgia and arthritis, and lower incidence

of new rheumatic symptoms among vedolizumab users

compared to placebo [88]. While there is a signal for

benefit of vedolizumab in CD-SpA, a significant limitation

of these analyses is the lack of uniform clinical pheno-

typing of inflammatory arthritis and prospective assign-

ment of disease activity indices, which will need to be

addressed in future analyses.

The strong genetic association of both SpA and IBD with

IL23R genetic variants and overlapping mechanisms

involving the IL23/IL17 axis highlighted the potential role of

specific blockade of this pathway in drug development. In

addition, elevation of IL-17, but not TNFa, has been reported

in CD-SpA compared to active CD alone [20]. However, the

translatability of these findings into therapeutic strategies

have so far been puzzling. Despite the efficacy of IL-17A

inhibitor therapy, secukinumab, for the treatment of AS [89],

it was not effective in the treatment of CD and may lead to a

higher rate of adverse events, including infections [90, 91].

Recent results in psoriatic arthritis reveal that IL-17A

blockade correlated with expansion of Candida albicans

with features of subclinical gut inflammation [92]. Another

potential explanation of this paradox comes from murine

models where the suppression of IL-17F, but not of IL-17A,

provided protection against colitis by inducing Treg cells

through modification of the intestinal microbiota [93, 94]. It

is postulated that low levels of IL-17 can be produced from

ILCs, Tcd, independent of IL-23 [95]. The homeostatic role

for this IL-23 independent IL-17 may reflect the unexpected

results of IL-17 blockade in CD.

In contrast to IL-17 blockade, anti-IL12/23 therapy,

ustekinumab is effective in the treatment of patients with

Crohn’s disease [96]. Ustekinumab is effective in patients

that have failed TNF antagonist therapy suggesting the

possibility of a distinct pathway of disease. It is not known

if this distinct pathway enriched in patients with CD-SpA.

Similarly, selective IL23 antagonist, risankizumab is in

development (ongoing phase 3 trials after successful phase

2 trials) for treatment of moderately-to-severely active CD

[97, 98]. Although ustekinumab is approved for psoriatic

arthritis and was found to be effective in treating con-

comitant PsA in IBD patients, suggesting its benefit for

CD-related peripheral SpA [99, 100], both ustekinumab

and risankizumab failed to demonstrate efficacy for AS

[101, 102]. Moreover, the switch from TNFa blockade to

anti-IL-12/23 blockade has been associated with the

unmasking of psoriatic arthritis in a small case series

within the psoriasis population [103]. Further studies are

needed to assess the impact of these pathways specifically

in patients with CD-SpA and tracked with meaningful

disease activity markers.

In addition to biologic therapy, small molecule inhibi-

tors of immune pathway are emerging as therapy for both

SpA and CD. In particular, the non-selective Janus kinase

(JAK) inhibitor, tofacitinib is approved for the treatment of

UC, RA and PsA [104-106] and a phase 3 trial in AS is

ongoing. While tofacitinib did not meet efficacy endpoints

in the phase 2 trials of Crohn’s disease [107], there was a

significant biochemical response and evidence from post-

hoc analyses suggest benefit in CD as well [108, 109]. In

initial trials, selective JAK-1 (filgotinib and upadacitinib)

and tyrosine kinase (TYK) inhibitors have shown efficacy

in Crohn’s disease [110]. Moreover, both filgotinib and

upadacitinib were found to be safe and effective in AS and

PsA in their respective phase 2 trials, while upadacitinib

met efficacy endpoints in a phase 3 study in PsA [111-113].

These highly encouraging results support enthusiasm for

specifically evaluating their efficacy in CD-SpA.

Despite similarities in pathogenesis, CD and SpA

maintain unique aspects of disease, which may need to be

therapeutically targeted independently. While both entities

may co-exist in a patient, it is possible that they do not

respond to common therapies and therefore strategies for

combining therapies need to be evaluated. Anecdotal cases

have raised the possibility of combining anti-a4b7 and

anti-TNFa blockade [108, 114]. Therapies directed towards

novel mechanistic targets are being studied which also

offer great potential. Sphingosine 1-phosphate (S1P)

modulation is one such strategy to block T cell egress from

lymph nodes into the circulation. In contrast to a4b7

blockade, this strategy may be able to block both tissue and

systemic inflammatory symptoms that depend on circulat-

ing lymphocytes [115]. In addition, anti-TL1A therapy is in

development for treatment of UC. Given the potential role

for TL1A in joint inflammation discussed above [46], it

remains to be evaluated whether this mechanism would be

effective in SpA as well. Finally, fecal microbiota trans-

plant (FMT) is under active investigation for the treatment

of IBD with preliminary success in the treatment of UC.

The impact of FMT on inflammatory arthritis is unknown.

Given the emerging knowledge of the potential role of

strain specific pathobionts in IBD-associated SpA, micro-

bial-based therapies may play an important role in modi-

fying clinical outcomes.

Conclusion

CD-SpA is a unique subset of CD with distinct clinical,

cellular, and microbial characteristics. Additional data are

needed using ASAS clinical diagnostic criteria and

674 J Gastroenterol (2020) 55:667–678

123

validated joint disease activity indexes to define the clinical

burden and therapeutic responses in this unique subset. Pre-

clinical and clinical data defining the link between the gut

microbiome and the inflammatory immune response in

CD-SpA has highlighted key pathways that can be thera-

peutically targeted. Combined with a multi-disciplinary

care team approach, future studies will help guide rational

selection of targeted therapies based on disease phenotype

and develop a precision medicine approach to spondy-

loarthritis in Crohn’s disease.

Compliance with ethical standards

Conflict of interest The authors declare no conflict of interest.

Open Access This article is licensed under a Creative Commons

Attribution 4.0 International License, which permits use, sharing,

adaptation, distribution and reproduction in any medium or format, as

long as you give appropriate credit to the original author(s) and the

source, provide a link to the Creative Commons licence, and indicate

if changes were made. The images or other third party material in this

article are included in the article’s Creative Commons licence, unless

indicated otherwise in a credit line to the material. If material is not

included in the article’s Creative Commons licence and your intended

use is not permitted by statutory regulation or exceeds the permitted

use, you will need to obtain permission directly from the copyright

holder. To view a copy of this licence, visit http://creativecommons.

org/licenses/by/4.0/.

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